Diabetic Cardiovascular Autonomic Neuropathy Research Articles

Urinary n-acetyl-beta-d-glucosaminidase Excretion: an Indicator of Neuropathy in Type 2 Diabetes

The established marker for tubular damage, urinary n-acetyl-beta-d-glucosaminidase is significantly increased in type 1 and 2 diabetes patients and is related to albuminuria and other diabetic complications. In this cross sectional study of type 2 diabetes patients with a history of albuminuria, we studied the relationship between excretion of n-acetyl-beta-d-glucosaminidase in urine and diabetic neuropathy.160 type 2 diabetes patients were screened for diabetic peripheral neuropathy and cardiovascular autonomic neuropathy. N-acetyl-beta-d-glucosaminidase excretion was detected in 24 h urine samples.Urinary excretion of n-acetyl-beta-d-glucosaminidase correlated significantly with -glucose control (fasting glucose r=0.18; p=0.04; HbA1c r=0.20; p=0.02) and urine albumin excretion (r=0.22; p=0.01). Binary regression analyses showed that increased urinary n-acetyl-beta-d-glucosaminidase concentration is an independent predictor for presence of clinical symptoms of peripheral neuropathy (OR 1.8 [95%CI 1.2-2.74] and vibration deficiency [OR 1.7; 95% CI 1.2-2.66]. There was also a significant negative association between urinary n-acetyl-beta-d-glucosaminidase and E/I-Ratio (r=-0.21, p<0.02) as well as the 30:15-Ratio (r=-0.24; p<0.01) of heart rate variability. Furthermore, increased n-acetyl-beta-d-glucosaminidase excretion independently predicted cardiovascular autonomic diabetic neuropathy with an OR for decreased E/I-Ratio of 1.7 [95%CI 1.1-2.75]; (p<0.02) and 30:15-Ratio:OR 2.4 [95% CI 1.26-4.45]; (p<0.01).Urinary n-acetyl-beta-d-glucosami-nidase excretion is an independent marker for diabetic peripheral and cardiovascular autonomic neuropathy in type 2 diabetic patients.

QT Variability Index Changes With Severity of Cardiovascular Autonomic Neuropathy

Cardiovascular autonomic neuropathy (CAN) has been frequently postulated to increase susceptibility to ventricular arrhythmias and sudden cardiac death in diabetic patients. The relation between the progression of CAN in diabetes and ventricular repolarization remains to be fully described. Therefore, this study examined QT interval variability and heart rate interbeat variability to identify any alterations of cardiac repolarization in diabetic patients in relation to severity of CAN. Seventy control participants without (CAN-) and 74 patients with CAN (CAN+) were enrolled in this study. Among 74 CAN + patients, 62 are early CAN + (eCAN +) , and 12 are definite CAN + (dCAN +) according to autonomic nervous system function tests as described by Ewing. The results showed that the QT variability index (QTVI) was significantly higher and positive in the dCAN + (0.51 ±1.32) group than in the eCAN + (-0.39 ±0.91) and CAN - (-0.54 ±0.72) groups. The QT variability to heart-rate variability ratio provides a measure of the balance between QT and heart interbeat variability. QTVI was more sensitive in identifying disease progression at all stages. Our study supports the hypothesis that QTVI could be used as a clinical test to identify early CAN and as a marker of CAN progression in diabetic patients and may help physicians in determining the best therapeutic strategy for these patients.

Diabetic cardiovascular autonomic neuropathy: clinical implications

Diabetic cardiovascular autonomic neuropathy (DCAN), the impairment of the autonomic balance of the cardiovascular system in the setting of diabetes mellitus (DM), is frequently observed in both Type 1 and 2 DM, has detrimental effects on the quality of life and portends increased mortality. Clinical manifestations include: resting heart rate disorders, exercise intolerance, intraoperative cardiovascular lability, orthostatic alterations in heart rate and blood pressure, QT-interval prolongation, abnormal diurnal and nocturnal blood pressure variation, silent myocardial ischemia and diabetic cardiomyopathy. Clinical tests for autonomic nervous system evaluation, heart rate variability analysis, autonomic innervation imaging techniques, microneurography and baroreflex analysis are the main diagnostic tools for DCAN detection. Aldose reductase inhibitors and antioxidants may be helpful in DCAN therapy, but a regular, more generalized and multifactorial approach should be adopted with inclusion of lifestyle modifications, strict glycemic control and treatment of concomitant traditional cardiovascular risk factors, in order to achieve the best therapeutic results. In the present review, the authors provide aspects of DCAN pathophysiology, clinical presentation, diagnosis and an algorithm regarding the evaluation and management of DCAN in DM patients.

What Do We Know and We Do Not Know About Cardiovascular Autonomic Neuropathy in Diabetes

Cardiovascular autonomic neuropathy (CAN) in diabetes is generally overlooked in practice, although awareness of its serious consequences is emerging. Challenges in understanding the complex, dynamic changes in the modulation of the sympathetic/parasympathetic systems' tone and their interactions with physiologic mechanisms regulating the control of heart rate, blood pressure, and other cardiovascular functions in the presence of acute hyper-or-hypoglycemic stress, other stressors or medication, and challenges with sensitive evaluations have contributed to lower CAN visibility compared with other diabetes complications. Yet, CAN is a significant cause of morbidity and mortality, due to a high-risk of cardiac arrhythmias, silent myocardial ischemia and sudden death. While striving for aggressive risk factor control in diabetes practice seemed intuitive, recent reports of major clinical trials undermine established thinking concerning glycemic control and cardiovascular risk. This review covers current understanding and gaps in that understanding of the clinical implications of CAN and prevention and treatment of CAN.

Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management

The Cardiovascular Autonomic Neuropathy (CAN) Subcommittee of the Toronto Consensus Panel on Diabetic Neuropathy worked to update CAN guidelines, with regard to epidemiology, clinical impact, diagnosis, usefulness of CAN testing, and management. CAN is the impairment of cardiovascular autonomic control in the setting of diabetes after exclusion of other causes. The prevalence of confirmed CAN is around 20%, and increases up to 65% with age and diabetes duration. Established risk factors for CAN are glycaemic control in type 1 and a combination of hypertension, dyslipidaemia, obesity, and glycaemic control in type 2 diabetes. CAN is a risk marker of mortality and cardiovascular morbidity, and possibly a progression promoter of diabetic nephropathy. Criteria for CAN diagnosis and staging are: (1) one abnormal cardiovagal test result identifies possible or early CAN; (2) at least two abnormal cardiovagal test results are required for definite or confirmed CAN; and (3) the presence of orthostatic hypotension in addition to abnormal heart rate test results identifies severe or advanced CAN. Progressive stages of CAN are associated with increasingly worse prognosis. CAN assessment is relevant in clinical practice for (1) diagnosis of CAN clinical forms, (2) detection and tailored treatment of CAN clinical correlates (e.g. tachycardia, orthostatic hypotension, non-dipping, QT interval prolongation), (3) risk stratification for diabetic complications and cardiovascular morbidity and mortality, and (4) modulation of targets of diabetes therapy. Evidence on the cost-effectiveness of CAN testing is lacking. Apart from the preventive role of intensive glycaemic control in type 1 diabetes, recommendations cannot be made for most therapeutic approaches to CAN.

Methods of investigation for cardiac autonomic dysfunction in human research studies

This consensus document provides evidence-based guidelines regarding the evaluation of diabetic cardiovascular autonomic neuropathy (CAN) for human research studies; the guidelines are the result of the work of the CAN Subcommittee of the Toronto Diabetic Neuropathy Expert Group. The subcommittee critically reviewed the limitations and strengths of the available diagnostic approaches for CAN and the need for developing new tests for autonomic function. It was concluded that the most sensitive and specific approaches currently available to evaluate CAN in clinical research are: (1) heart rate variability, (2) baroreflex sensitivity, (3) muscle sympathetic nerve activity, (4) plasma catecholamines, and (5) heart sympathetic imaging. It was also recommended that efforts should be undertaken to develop new non-invasive and safe CAN tests to be used in clinical research, with higher sensitivity and specificity, for studying the pathophysiology of CAN and evaluating new therapeutic approaches.

Long-term predictive power of simple function tests for cardiovascular autonomic neuropathy in diabetes: a population-based study

No consensus exists on which test is optimal in screening for cardiovascular autonomic neuropathy in diabetic patients. The long-term predictive power of five simple function tests with regard to all-cause mortality in individuals with diabetes from the general population was assessed. The diabetic population in the municipality of Horsens, Denmark, was delineated by the prescription method, and an age- and gender-stratified sample of 240 diabetic persons was randomly selected. Five function tests were conducted: Valsalva ratio, heart rate response to standing (30:15 ratio), expiration/inspiration ratio (E/I ratio), ortostatic blood pressure response (Orto BP) and increase in diastolic blood pressure during sustained handgrip. After a 15½-year follow-up period, vital statistics were obtained from the Danish Civil Registration System. One hundred and seventy eight persons participated, 44% women, 40% type 1 diabetes, mean age 58.9 (SD 10.2) years. In Cox regression analysis, adjusting for age and gender, each test had a significant predictive effect on mortality (all P<0.05). In the multivariate analysis, only Valsalva ratio (P=0.0017), 30:15 ratio (P=0.037) and handgrip (P=0.037) were predictors of survival. As a binary variable, the presence of CAN was associated with a relative risk of all-cause death of 2.85 (95%CI: 1.75-4.65, P=0.00003). In the period following the first 5years, CAN's predictive value remained significant. This study indicates that Valsalva, 30:15 ratio and handgrip, but not E/I ratio and Orto BP, have an independent predictive value with regard to long-term all-cause mortality. Baseline function tests hold prognostic information after at least 5years.

Cardiovascular autonomic neuropathy contributes to left ventricular diastolic dysfunction in subjects with Type 2 diabetes and impaired glucose tolerance undergoing coronary angiography

Left ventricular diastolic dysfunction is considered a precursor of diabetic cardiomyopathy, while diabetic cardiovascular autonomic neuropathy is associated with an increased risk of mortality. This study aimed to evaluate the association between left ventricular diastolic dysfunction and cardiovascular autonomic neuropathy, both diagnosed according to the current guidelines. We evaluated 145 patients referred for an elective coronary angiography, 52 of whom had Type 2 diabetes and 48 had impaired glucose tolerance, while 45 subjects had normal glucose tolerance. Cardiovascular autonomic neuropathy was diagnosed using autonomic function tests, while left ventricular diastolic dysfunction was verified by tissue Doppler imaging echocardiography. Cardiovascular autonomic neuropathy was diagnosed in 15 (28.8%) patients with Type 2 diabetes and in six (12.5%) individuals with impaired glucose tolerance. The rates of left ventricular diastolic dysfunction were 81 and 33% in patients with and without cardiovascular autonomic neuropathy, respectively (P < 0.001). In the cardiovascular autonomic neuropathy group (n = 21), early diastolic relaxation velocity (Em) was significantly reduced (5.4 ± 0.9 vs. 7.3 ± 2.1 cm/s; P < 0.001) and the E/Em ratio was significantly higher (13.6 ± 4.6 vs. 10.3 ± 3.4 cm/s, P < 0.001) as compared with the group without cardiovascular autonomic neuropathy (n = 79). These findings remained significant after adjustment for age, sex, coronary artery disease, hypertension and HbA(1c) . A severe form of left ventricular diastolic dysfunction was observed in 33 and 15% of patients with and without cardiovascular autonomic neuropathy, respectively (P = 0.001). Cardiovascular autonomic neuropathy is associated with a higher prevalence and a more severe form of left ventricular diastolic dysfunction in patients with diabetes or impaired glucose tolerance undergoing coronary angiography. Because both cardiovascular autonomic neuropathy and left ventricular diastolic dysfunction are associated with increased cardiovascular morbidity and mortality, screening for patients with left ventricular diastolic dysfunction and cardiovascular autonomic neuropathy with diabetes or impaired glucose tolerance may identify those at high risk.

Development of an analytic standard for evaluating heart rate variability in cardiovascular autonomic neuropathy in diabetes: comparison of short-term spectral analysis with Ewing's standard battery of reflex tests as reference method

Development of an analytic standard for evaluating heart rate variability in cardiovascular autonomic neuropathy in diabetes: comparison of short-term spectral analysis with Ewing's standard battery of reflex tests as reference method

Neuropad as a diagnostic tool for diabetic autonomic and sensorimotor neuropathy

The aim of the present study was to determine the diagnostic accuracy of the Neuropad sudomotor test for diabetic cardiovascular autonomic neuropathy (CAN) and diabetic polyneuropathy (DPN), the latter assessed using a multi-level diagnostic approach. In 51 diabetic patients, CAN, symptoms and signs of DPN, vibration perception threshold (VPT), cold (CTT) and warm thermal perception thresholds (WTT) were measured. Neuropad response was determined as normal (complete colour change) or abnormal (absent or incomplete colour change). The time until the complete colour change (CCC time) was recorded. CCC time showed significant correlations with all the neurological parameters, the strongest of which were with Valsalva ratio (rho = -0.64, P < 0.0001), symptoms of DPN (rho = 0.66, P < 0.0001), postural hypotension (rho = 0.54, P = 0.0001) and CTT (rho = -0.54, P = 0.0001). CCC time showed moderate diagnostic accuracy for both CAN and DPN: the areas under the receiver operating characteristic (ROC) curves were 0.71 and 0.76, respectively. The diagnostic characteristics of three cut-off values of CCC time, identified by ROC analysis (i.e. 10, 15 and 18 min), were analysed. Compared with 10 min, the 15-min cut-off value provided better specificity (from 27% to 52% and from 31% to 62% for CAN and DPN, respectively) and a better likelihood ratio for negative result (from 0.67 to 0.34 and from 0.58 to 0.33) without lowering sensitivity (from 82% to 82% and from 85% to 80%). Neuropad is a reliable diagnostic tool for both CAN and DPN, albeit of only moderate accuracy. Extending the observation period to 15 min provides greater diagnostic usefulness.

Desflurane-induced hemodynamic changes in patients with diabetic cardiovascular autonomic neuropathy.

Diabetic cardiovascular autonomic neuropathy (CAN) causes perioperative cardiovascular instability. A rapid increase in the desflurane concentration induces tachycardia and hypertension (HTN). This study examined the effects of the cardiovascular response to desflurane on patients with diabetic CAN. Forty diabetes mellitus (DM) patients with CAN were divided two groups: one with HTN (DM+HTN group, n = 17) and one without HTN (DM group, n = 23). The control group (n = 20) was composed of healthy patients without DM or HTN. In each group, the concentration of desflurane inspired was increased abruptly to 12.0 vol% 2 minutes after a thiopental injection. The target was to produce an end-tidal concentration of desflurane of 10.0 vol%, which was maintained until the end of the study by adjusting the vaporizer dial setting. The heart rate (HR), mean arterial pressure (MAP), and cardiac index (CI) were measured. The HR, MAP and CI increased significantly in all three groups when compared with the baseline (P<0.05). Additionally, the HR and MAP showed did not differ among the three groups at any of sampling times. However, the CI of the DM group and the DM+HTN group differed when compared with the control group at 90 and 120 seconds after intubation (P<0.05). In diabetic patients with CAN, the hemodynamic responses to a rapid increase in desflurane concentration are similar to those in non-diabetic patients before endotracheal intubation. However, after endotracheal intubation, increments in CI are blunted in diabetic patients with CAN.

Neuropatia autonômica cardiovascular diabética: fatores de risco, impacto clínico e diagnóstico precoce

Cardiovascular autonomic neuropathy (CAN) is one of the most clinically significant complications of diabetes mellitus (DM), but one of the least frequently diagnosed. In this review, we discuss the major risk factors for the development and progression of CAN in patients with DM, the natural history of autonomic neuropathy and its impact on cardiovascular disease in DM, as well as the tests for the early diagnosis and staging of CAN in the clinical practice. The bibliographic research was based on two databases: Medline and Tripdatabase, with the following descriptors: diabetic cardiovascular autonomic neuropathy and cardiovascular autonomic neuropathy and diabetes. We selected English and German articles, written between 1998 and 2007. In its initial stages (early and intermediate), CAN may be diagnosed and reversed. However, in advanced cases (severe stage), the only treatment that remains is a symptomatic one. CAN is associated with higher cardiovascular morbidity and mortality rates and poor quality of life in diabetic individuals.

Cardiac autonomic diabetic neuropathy

Cardiovascular autonomic diabetic neuropathy (CADN) is one of the most common diabetes-associated complications. Disturbed heart rate variability (HRV) is very often the earliest symptom, even in clinically asymptomatic patients. The following article offers a topical overview for those working or interested in the fields of diabetology and cardiology.

Could we predict asymptomatic cardiovascular autonomic neuropathy in type 1 diabetic patients attending out-patients clinics?

Diabetic cardiovascular autonomic neuropathy (CAN) is associated with increased morbidity and mortality. This complication may be asymptomatic for a long time. The aim of this study was to assess the prevalence, severity and predictors of asymptomatic CAN in patients with type 1 diabetes mellitus (DM1). 107 patients with DM1 were enrolled: 52 men and 55 women aged 39.8 +/- 12.4 years (18-72), duration of DM 16.6 +/- 9.5 years (0.5-43), age at DM manifestation 23.5 +/- 12.8 years (1-54) and BMI 25.1 +/- 3.2 (18.9-33.91). CAN was assessed using standard cardiovascular reflex tests (Ewing battery) and the patients were divided into three groups according to the results: Group 0, without CAN; Group I, 1(st) degree CAN; Group II, 2(nd) degree CAN. We assessed the most frequent relationships between CAN and chronic complications, episodes of severe hypoglycemia, time-related parameters (age of patients, duration of diabetes, age at manifestation), glycosylated hemoglobin (HbA(1)c), BMI, cardiovascular diseases and blood pressure, and determined the predictability of CAN on the basis of these relationships. Only 50 of the 107 patients (46%) showed no CAN. We found 1(st) degree CAN in 38 patients (36%) and 2(nd) degree CAN in 19 (18%). CAN correlated more significantly with the duration of diabetes (p < 0.001) than with age (p < 0.05). The relationship between CAN and HbA(1)c was on the borderline of statistical significance (p = 0.053). We found a positive correlation between CAN and the presence of chronic complications [peripheral neuropathy (p < 0.001), retinopathy (p < 0.001), and some markers of nephropathy: creatinine (p < 0.03), albuminuria (p < 0.01)]. Although blood pressure was within the physiological range (124.2/74.5 +/- 11.5/7.8 mmHg) in all patients, a positive correlation with CAN was confirmed (p < 0.05). No relationship with occurrence of severe hypoglycemia was found. According to our results, asymptomatic CAN is very frequent in patients with DM1. By using multifactorial logistic regression (step-wise) analysis we demonstrated that if albuminuria, peripheral neuropathy and elevated systolic BP are present simultaneously, there is a high probability that the patient also has CAN (84.9% of initial group correctly predicted, p < 0.001).

Diabetic Cardiovascular Autonomic Neuropathy

Cardiovascular autonomic neuropathy (CAN) is the most frequent complication of diabetes and one of the major components of diabetic dysautonomia. CAN occurs early in the course of diabetes, and several pathophysiological factors are involved. It is associated with an impairment in cardiovascular prognosis. Cardiac autonomic function should be assessed in most diabetic patients as it contributes to the evaluation of cardiovascular risk. The presence of CAN should lead to further awareness of possible complications and optimal control of risk factors. Pathophysiology As for peripheral neuropathy, both metabolic and vascular mechanisms are probably involved in the pathogenesis of diabetic CAN. Metabolic changes consecutive to chronic hyperglycaemia include polyol pathway activation, oxidative stress, accumulation of advanced glycated endproducts, proteine kinase C activation and impairment of essential fatty acid metabolism. As for the role of microvascular factors, reduced endoneurial blood flow and oxygen tension, endothelial dysfunction, increased capillary permeability that may induce endoneurial oedema and rheological changes have been shown in experimental diabetes. In addition, oxidative stress may be the link between the metabolic and vascular hypotheses.1 Malnutrition may also be implicated, as suggested in Asian populations.2 Carbohydrate intake may also impair vagosympathetic balance.3 Finally, in patients with type 1 diabetes, several studies stand in favour of immunological factors.4

Impact of diabetic polyneuropathy and cardiovascular autonomic neuropathy on the excretion of urinary 8-epi-PGF2α and its metabolites (2, 3-dinor and 2, 3-dinor-5, 6-dihydro)

The objective of this study was to establish if diabetes in the presence of polyneuropathy (PN) and/or cardiovascular autonomic neuropathy (CAN) is associated with alterations in the amounts of 8-epi-PGF2α (IP) and its metabolites including 2, 3-dinor-8-epi-PGF2α (dinor-IP) and 2, 3-dinor-5, 6 dihydro-8-epi-PGF2α (dinor-dihydro-IP) in urine. Mass spectrometric separation showed that excretion of IP was similar in the PN+/CAN − and PN+/CAN+ groups but higher than in the PN − /CAN − group (n = 103, 22 and 60, respectively; P < 0.05). By contrast, excretion of dinor-IP or dinor-dihydro-IP were similar in the PN − /CAN − and PN+/CAN − groups but higher than in PN+/CAN+ group. Correlations were obtained between IP and dinor-IP or dinor-dihydro-IP (r = 0.30; P < 0.001 and r = 0.31; P < 0.001, respectively). A significant association was also observed between dinor-IP and dinor-dihydro-IP (r = 0.48; P < 0.001). In conclusion, these biomarkers should prove useful in studies evaluating the impact of therapeutic drugs or antioxidant interventions aimed at delaying the onset of diabetic complications.

Cross-spectral analysis of cardiovascular variables in supine diabetic patients

Cardiovascular autonomic neuropathy in diabetes is associated with a high risk of mortality, which makes its early identification clinically important. An easy method for identification of subjects with autonomic dysfunction would be of clinical benefit. We evaluated the autonomic function in 28 diabetic patients and 21 control subjects recording 12 min time series of heart period (RR) and systolic arterial pressure (SAP, Finapres) during supine rest and 60 degrees head-up tilt. The power of the high (respiratory) and low (LF approximately 0.1 Hz) frequency oscillations was quantified by spectral analysis. The central frequency of the LF oscillations (LF_freq), phase shift, and the transfer function gain between RR interval and SAP fluctuations were provided by cross-spectral analysis, and measured at the point of maximal coherence. In the supine position 15 patients (LF-) displayed atypical LF variability with the LF_freq being shifted towards lower frequencies (about 0.06 Hz). They also showed larger phase angle, lower values or even absence of coherence and smaller transfer function gain between RR and SAP fluctuations. 13 patients (LF+) and the controls showed the LF_freq around 0.1 Hz, higher coherence and transfer function gain values. The orthostatic maneuver induced the expected changes in the spectral parameters (increase in the LF components of both RR and SAP and decrease in the HF variability of RR) into the LF+ patients and all the control subjects and abnormal response in the other 15 LF-patients. These findings indicate that diabetic subjects with uncharacteristic response to the orthostatic test present abnormal LF variability already in the supine position. Crossspectral parameters while supine may be used for the identification of these subjects.

Clinical consequences of cardiovascular autonomic neuropathy in diabetic patients.

A wide range of clinical consequences of cardiovascular autonomic neuropathy (CAN) can be observed in diabetic patients and contributes to the clinical picture of the diabetic heart. Resting heart rate and cardiovascular reflexes as well as circadian heart rate variability may be altered by CAN in diabetes. Moreover, blood pressure is also influenced by sympathovagal imbalance. Postural hypotension is a clinical characteristic in diabetic subjects with CAN. Painless myocardial infarction, ischaemia and left ventricular dysfunction are also observed in some cases. Impairment of cardiac parasympathetic and sympathetic innervation as well as QT-interval prolongation may play a partial role in the pathogenic mechanism of sudden unexpected death in diabetic patients. The risk of surgical intervention and that of anaesthesia are increased due to abnormal cardiovascular reactions. Clinical symptoms and signs of CAN should be assessed as severe diabetic complication and the therapy is difficult in some cases. Taken together, symptoms and signs of CAN carry a poor prognosis in diabetic patients.

Time-Domain Analysis of Heart Rate Variability in Diabetic Patients with and without Autonomic Neuropathy

The normal heart rate is determined by dynamic interaction between the spontaneous cardiac impulse generated by the sinoatrial (SA) node and conflicting influences of the sympathetic and parasympathetic nervous systems on the conducting tissue of the heart. The rate of spontaneous depolarization of the SA node is itself affected by its metabolic milieu and in the longer term, by hormonal influences. Normal resting heart rate is maintained by the tonic influence of the parasympathetic vagus nerve, and acceleration of the heart rate is affected both by the inhibition of vagal influence and the stimulation of the sympathetic nervous system. The activity of the autonomic is also governed by moment-to-moment changes in blood pressure and respiration, which alter heart rate continuously. The resultant heart rate is the summation of all these influences and thus inherently unpredictable on a beat-to-beat basis. Recent advances in technology have enabled accurate recordings and the automated analysis of 24-hour ECG to detect beat-to-beat variability, providing not only more detailed, but much more accurate and precise information than the earlier tests. Heart rate variability (HRV) decreases with age, and shows a circadian variation, being maximum during sleep. It is also rate dependant, the heart rate showing more variability at lower heart rates. The loss of this beat-to-beat variability is a sign of disease. It has long been known that cardiovascular autonomic diabetic neuropathy (CADN) is associated with a loss of heart rate variability. These patients have a poor cardiovascular prognosis, with a 5-year mortality greater than 50%. Some of this may be attributed to micro- or macrovascular disease, however, a recent study has shown the relatively poor prognosis of patients with CADN in the absence of clinically detectable micro- or macrovascular conditions. Clinically detectable autonomic failure is usually evident many years or decades after the onset of diabetes. It is likely that these patients develop subtle deficits in HRV much earlier, and these may include diminution in time-domain analysis. Detection of such changes may be used as markers of pathology, particularly to study the benefits of therapeutic interventions. Thus, the aim of this work was to study HRV in diabetic patients with clinical and sub-clinical autonomic neuropathy (AN), and to determine whether HRV in patients with sub-clinical AN is abnormal in comparison to normal controls.

Time- and frequency-domain estimation of early diabetic cardiovascular autonomic neuropathy.

The risk related to cardiovascular autonomic neuropathy dysautonomia should lead to a specific assessment of this complication of diabetes. The aim of this study was to estimate the accuracy of a battery of blood pressure (BP) and heart rate (HR) variability indexes obtained in different subgroups of diabetic subjects classified according to the conventional laboratory autonomic function tests (Ewing scores). Blood pressure was measured continuously at the finger level with a Finapres monitor while subjects were in the supine position and again while they were standing. Pulse intervals were derived from BP recordings and were taken as surrogates for R-R intervals. Subjects with borderline or definite cardiovascular autonomic neuropathy showed a similar degree of alterations of both HR and BP variability (spectral measures) and in the relationship between BP and HR (cross-spectral and sequence analysis). Subjects with no evidence of cardiovascular autonomic neuropathy on the basis of the conventional tests showed an altered relationship between BP and HR. This baroreceptor-HR reflex dysfunction could represent an early stage of cardiovascular autonomic neuropathy undetected by the conventional tests. The areas under the receiver operating characteristic plots indicated that the high-frequency peak of pulse interval was highly discriminant in the supine and standing positions. The cross-spectral analysis showed the best discrimination for the gain in the high-frequency range. For the sequence analysis, the slope was the best discriminant factor for any degree of cardiovascular autonomic neuropathy. In conclusion, these estimates of baroreceptor-HR function may provide a powerful tool for assessing cardiovascular autonomic neuropathy at any stage, including the early stage, which is not detected by the conventional tests.